Tendon tears are common musculoskeletal injuries that heal without restoration of the functional structure. Failure of healing tendons to restore th functional structure leads to progression of injury and high incidence of retear after surgical repair. Scarless tendon healing, with restored native tissue properties, could improve surgical outcome or eliminate the need for surgical repair altogether, but is not typically observed in postnatal mammals. The discovery that adult Murphy Roths Large (MRL/MpJ) mice exhibit a regenerative capacity has distinguished this mouse strain as an exciting model to investigate mechanisms that underlie adult regenerative healing. Investigation into the regenerative mechanisms of MRL/MpJ mice has generated hypotheses that implicate both, the systemic and local tissue level, but no conclusive data exists. The proposed studies interrogate the contribution of the systemic environment of the MRL/MpJ mouse and the local environment of its tendon to scarless tendon healing. Our hypothesis is that scarless healing in MRL/MpJ tendons is mediated by a unique provisional extracellular matrix (ECM) that promotes improved alignment and proliferation of matrix producing cells but does not ultimately lead to excessive matrix deposition due to increased catabolic activity of Matrix Metalloproteinase 9 (MMP9). In addition to our published data that show that MRL/MpJ mice exhibit improved healing in midsubstance punch injuries, additional evidence that supports this novel hypothesis includes: (1) data that show that the provisional ECM in regenerative MRL/MpJ mice differs in structure and composition than the provisional ECM in healing B6 tendons? (2) data that show that during the early phases of healing, MRL/MpJ tendons exhibit increased cell proliferation and improved alignment in the context of this distinctly different and better aligned provisional ECM? and (3) correlated data that show increased expression of MMP9 and a provisional ECM that is replaced by a better aligned long term ECM. We propose to interrogate the systemic and local factors that contribute to synthesis of MRL/MpJ's unique provisional ECM (Aim 2) and elucidate the role of this provisional ECM in modulating the cellular response (Aim 1). We will also explore the therapeutic potential of the provisional ECM derived from MRL/MpJ healing tendons to promote scarless tendon healing in scarmediated B6 mice (Aim 3). Novel microsurgical techniques and inbred mouse strains are utilized to uncouple the contribution of the systemic environment and the tendon to scarless tendon healing. Tendon organ culture is also employed to determine the role of the provisional ECM from regenerative MRL/MpJ mice in modulating the cellular activity that leads to scarless tendon healing. These studies set the foundation for development of therapeutic interventions by isolating the contributions of the innate tendon and the systemic environment to scarless tendon healing. The potential utility of MRL/MpJ's provisional ECM as a therapeutic intervention that harnesses the biological and structural queues that lead to scarless tendon healing could be highly impactful for the field of tendon tissue engineering.